Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

“Ecstasy” [(±)-3,4-methylenedioxymethamphetamine, MDMA, XTC, X, E] is a psychoactive recreational hallucinogenic substance and a major worldwide drug of abuse. Several reports raised the concern that MDMA has the ability to induce neurotoxic effects both in laboratory animals and humans. Despite more than two decades of research, the mechanisms by which MDMA is neurotoxic are still to be fully elucidated. MDMA induces serotonergic terminal loss in rats and also in some mice strains, but also a broader neuronal degeneration throughout several brain areas such as the cortex, hippocampus, and striatum. Meanwhile, in human “ecstasy” abusers, there are evidences for deficits in seronergic biochemical markers, which correlate with long-term impairments in memory and learning. There are several factors that contribute to MDMA-induced neurotoxicity, namely, hyperthermia, monoamine oxidase metabolism of dopamine and serotonin, dopamine oxidation, the serotonin transporter action, nitric oxide, and the formation of peroxinitrite, glutamate excitotoxicity, serotonin 2A receptor agonism, and, importantly, the formation of MDMA neurotoxic metabolites. The present review covered the following topics: history and epidemiology, pharmacological mechanisms, metabolic pathways and the influence of isoenzyme genetic polymorphisms, as well as the acute effects of MDMA in laboratory animals and humans, with a special focus on MDMA-induced neurotoxic effects at the cellular and molecular level. The main aim of this review was to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA neurotoxicity, which can help in the development of therapeutic approaches to prevent or treat the long-term neuropsychiatric complications of MDMA abuse in humans.     

Mazindol Attenuates the 3,4-Methylenedioxymethamphetamine-Induced Formation of Hydroxyl Radicals and Long-Term Depletion of Serotonin in the Striatum

The formation of hydroxyl radicals following the systemic administration of 3,4-methylenedioxymethamphetamine (MDMA) was studied in the striatum of the rat by quantifying the stable adducts of salicylic acid and D-phenylalanine, namely, 2,3-dihydroxybenzoic acid (2,3-DHBA) and p-tyrosine, respectively. The repeated administration of MDMA produced a sustained increase in the extracellular concentration of 2,3-DHBA and p-tyrosine, as well as dopamine. The MDMA-induced increase in the extracellular concentration of both dopamine and 2,3-DHBA was suppressed in rats treated with mazindol, a dopamine uptake inhibitor. Mazindol also attenuated the long-term depletion of serotonin (5-HT) in the striatum produced by MDMA without altering the acute hyperthermic response to MDMA. These results are supportive of the view that MDMA produces a dopamine-dependent increase in the formation of hydroxyl radicals in the striatum that may contribute to the mechanism whereby MDMA produces a long-term depletion of brain 5-HT content.     

Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT_2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT_2B receptors to the reinforcing properties of MDMA.We show here that 5-HT_2B ^−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT_2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT_2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT_2B receptor-independent behavioral effects.These results underpin the importance of 5-HT_2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.     

甲基苯丙胺的急性和慢性作用机理的研究进展

甲基苯丙胺是一种被广泛使用的神经兴奋剂,它可以使人兴奋,产生欣快感并引起幻觉。这主要是因为脑内的多巴胺和5-羟色胺急剧大量增加所致。长期使用甲基苯丙胺,会对多巴胺和5-羟色胺神经末梢产生持续性的损伤。甲基苯丙胺毒性机理包括兴奋性毒性、线粒体损伤、氧化应激、代谢改变以及炎症反应等,这些均会造成神经末梢损伤。综述了甲基苯丙胺造成神经末梢急性和慢性损伤的机制。     

Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus

Aims

Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages 5HT nerve endings of the hippocampus.

Main methods

The status of 5HT nerve endings in the hippocampus of female C57BL mice was assessed through measures of 5HT by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of 5HT nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4.

Key findings

Mephedrone alone did not cause persistent reductions in the levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5HT nerve endings to an extent that was different from either drug alone.

Significance

Mephedrone does not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together.     

Short- and long-term effects of MDMA ("ecstasy") on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a commonly abused drug which has been shown to be neurotoxic to serotonergic neurons in many species. The exact mechanism responsible for the neurotoxicity of MDMA is, however, poorly understood. In this study, the effects of MDMA on the synaptosomal and vesicular uptake of neurotransmitters were investigated. Our results show that MDMA (0.5-20 microM) reduces both synaptosomal and vesicular uptake of serotonin and dopamine in a dose dependent manner in vitro, while the uptake of glutamate and gamma-aminobutyric acid (GABA) remains unaffected. Ex vivo experiments support the importance of the monoamines, with predominant dopaminergic inhibition at short-term exposure (3 x 15 mg/kg; 2-h intervals), and exclusively serotonergic inhibition at long-term exposure (2 x 10 mg/kg per day; 4 days). This study also compares MDMA and the structurally related antidepressant paroxetine, in an attempt to reveal possible cellular mechanisms for the serotonergic toxicity of MDMA. One important difference between paroxetine and MDMA is that only MDMA has the capability of inhibiting vesicular uptake of monoamines at doses used. We suggest that inhibition of the vesicular monoamine transporter-2, and a following increase in cytoplasmatic monoamine concentrations, might be crucial for the neurotoxic effect of MDMA.     

Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity

The neurotoxicity of MDMA or "Ecstasy" in rats is selectively serotonergic, while in mice it is both dopaminergic and serotonergic. MDMA metabolism may play a key role in this neurotoxicity. The function of serotonin and dopamine transporter and the effect of MDMA and its metabolites on them are essential to understand MDMA neurotoxicity. The aim of the present study was to investigate and compare the effects of MDMA and its metabolite alpha-methyldopamine (MeDA) on several molecular targets, mainly the dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA had no affinity for the serotonin transporter but competed with serotonin for its uptake. It had no persistent effects on the functionalism of the serotonin transporter, in contrast to the effect of MDMA. Moreover, MeDA inhibited the uptake of dopamine into the serotonergic terminal and also MAO(B) activity. MeDA inhibited dopamine uptake with a lower IC(50) value than MDMA. After drug washout, the inhibition by MeDA persisted while that of MDMA was significantly reduced. The effect of MDMA on the dopamine transporter is related with dopamine release from vesicular stores, as this inhibition disappeared in reserpine-treated animals. However, the effect of MeDA seems to be a persistent conformational change of this transporter. Moreover, in contrast with MDMA, MeDA did not show affinity for nicotinic receptors, so no effects of MeDA derived from these interactions can be expected. The metabolite reduced cell viability at lower concentrations than MDMA. Apoptosis plays a key role in MDMA induced cellular toxicity but necrosis is the major process involved in MeDA cytotoxicity. We conclude that MeDA could protect against the serotonergic lesion induced by MDMA but potentiate the dopaminergic lesion as a result of the persistent blockade of the dopamine transporter induced this metabolite.     

Multiple molecular and neuropharmacological effects of MDMA (Ecstasy)

3,4-Methylenedioxymethamphetamine (MDMA), commonly referred to as Ecstasy, is a widely abused, psychoactive recreational drug, which induces short- and long-term neuropsychiatric behaviors. This drug is neurotoxic to serotonergic neurons in vivo, and induces programmed cell death in cultured human serotonergic cells and rat neocortical neurons. Over the years it has been shown that MDMA alters the release of several neurotransmitters in the brain, it induces recompartmentation of intracellular serotonin and c-fos, and modifies the expression of a few genes. Recently, we observed changes in gene expression in mice treated with MDMA, and cloned and sequenced 11 cDNAs thus affected (4 correspond to known and 7 to unknown genes). The effect of MDMA on two of these genes, GABA transporter 1 and synaptotagmin IV was studied in detail. Characterization of the relationship between a given gene and certain physiological or behavioral effects of MDMA could shed light on the mechanism of the drug's action. However, establishing such a connection is difficult for several reasons, including that serotonergic neurons are not the only cells affected by MDMA. In this review, molecular and neurochemical events that occur in the brain following exposure to MDMA, and link between the observed molecular changes with known physiological effects of the drug are discussed. It is indicated that MDMA alters the expression of several proteins involved in GABA neurotransmission, thus having critical effect on thermoregulation and MDMA acute toxicity. This analysis should facilitate development of novel approaches to prevent deleterious effects, especially mortality induced by MDMA and other abused psychostimulants.     

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), methamphetamine and D-amphetamine

Amphetamine ('Speed'), methamphetamine ('Ice') and its congener 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity.     

Memory impairment and hippocampus specific protein oxidation induced by ethanol intake and 3, 4‐Methylenedioxymethamphetamine (MDMA) in mice

Ethanol and 3, 4‐Methylenedioxymethamphetamine (MDMA) are popular recreational drugs widely abused by adolescents that may induce neurotoxic processes associated with behavioural alterations. Adolescent CD1 mice were subjected to ethanol intake using the drinking in the dark (DID) procedure, acute MDMA or a combination. Considering that both drugs of abuse cause oxidative stress in the brain, protein oxidative damage in different brain areas was analysed 72 h after treatment using a proteomic approach. Damage to specific proteins in treated animals was significant in the hippocampus but not in the prefrontal cortex. The damaged hippocampus proteins were then identified by mass spectrometry, revealing their involvement in energy metabolism, structural function, axonal outgrowth and stability, and neurotransmitter release. Mice treated with MDMA displayed higher oxidative damage than ethanol‐treated mice. To determine whether this oxidative damage was affecting hippocampus activity, declarative memory was evaluated at 72 h after treatment using the object recognition assay and the radial arm maze. Although acquisition in the radial arm maze was not impaired by ethanol intake, MDMA treatment impaired long‐term memory in both tests. Therefore, oxidative damage to specific proteins observed under MDMA treatment affects important cellular function on the hippocampus that may contribute to declarative memory deficits.     

Ketamine pretreatment exacerbated 3,4-methylenedioxymethamphetamine-induced central dopamine toxicity

Currently, joint use of ketamine and 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) represents a specific combination of polydrug abuse. Long-lasting and even aggravated central neuronal toxicity associated with mixing ketamine and MDMA use is of special concern. This study was undertaken to examine the modulating effects of ketamine treatment on later MDMA-induced dopamine and serotonin neurotoxicity. We found that repeated administration of ketamine (50 mg/kg x 7) at 1.5-h intervals did not render observable dopamine or serotonin depletion in catecholaminergic target regions examined. In contrast, three consecutive doses of MDMA (20 mg/kg each) at 2-h intervals produced long-lasting dopamine and serotonin depletions in striatum, nucleus accumbens and prefrontal cortex. More importantly, pretreatment with binge doses of ketamine (50 mg/kg x 7 at 1.5-h intervals) 12 h prior to the MDMA dosing regimen (20 mg/kg x 3 at 2-h intervals) aggravated the MDMA-induced dopaminergic toxicity. Nonetheless, such binge doses of ketamine treatment did not affect MDMA-induced serotonergic toxicity. These results, taken together, indicate that binge use of ketamine specifically enhances the MDMA-induced central dopaminergic neurotoxicity in adult mouse brain.     

Acute effects of 3,4-methylenedioxymethamphetamine on brain serotonin synthesis in the dog studied by positron emission tomography

The influence of an acute dose (2 mg/kg; i.v.; infused over 10 min) of 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) on the brain serotonin synthesis in the dog was assessed using alpha [11C]methyl-L-tryptophan and positron emission tomography. The rate of serotonin synthesis measured 1 h after injection of MDMA was six times greater than the base line (before MDMA) synthesis. Five hours after the MDMA injection, serotonin synthesis was about one half that at the base line, and about one thirteenth of the synthesis at 1 h after MDMA. A large increase seen 1 h after MDMA probably relates to the large release of serotonin by MDMA and reflects an attempt of the serotonergic system to replenish released serotonin. This probably correlates with the mood changes reported by humans after MDMA intake. Decrease observed 5 h after MDMA, in part, probably relates to the inhibitory effects of the released serotonin, which could act on the activity of tryptophan hydroxylase directly or indirectly via other monoaminergic systems (e.g. dopaminergic).     

Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats.

Club drug abuse is a growing problem in the United States. Beyond addiction and toxicity are endocrine effects which are not well characterized. Specifically, the changes in appetite following exposure to drugs of abuse are an interesting but poorly understood phenomenon. Serum hormones such as leptin, ghrelin, growth hormone (GH), and neuropeptide-Y (NP-Y) are known to affect appetite, but have not been studied extensively with drugs of abuse. In this work, we examine the effects of club drugs 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) and methamphetamine (METH) (doses of 5, 20 and 40 mg/kg) on serum concentrations of these hormones in adult male Sprague-Dawley rats 6, 12, 24 and 48 hours after drug administration. In a dose-dependent manner, MDMA was shown to cause transient significant decreases in serum leptin and GH followed by a base line recovery after 24 hours. Conversely, serum ghrelin increased and normalized after 24 hours. Interestingly, serum NP-Y showed a steady decrease in both treatment of MDMA and METH at different time points and dosages. In humans, abuse of these drugs reduces eating. As evident from these data, acute administration of METH and MDMA had significant effects on different serum hormone levels involved in appetite regulation. Future studies should be performed to see how chronic, low dose drug administration would affect hormone levels and try to answer questions about the physiological mechanisms involved in the anorexic paradigm observed in drug use.     

Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity

The mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) produces serotonin (5-HT) neurotoxicity is unknown but considerable evidence suggests that endogenous brain dopamine (DA) is involved. However, it has recently become apparent that some of the data implicating brain DA in MDMA neurotoxicity may be confounded by drug effects on thermoregulation. The purpose of the present studies was to examine the role of DA in MDMA neurotoxicity, while controlling for possible confounding effects of drug- induced changes in core temperature. Rats were treated with reserpine, alone and in combination with alpha-methyl-p -tyrosine (AMPT), to deplete vesicular and cytoplasmic stores of DA. When drug-induced hypothermia was averted (by raising ambient temperature), the 5-HT neuroprotective effects of reserpine and AMPT were no longer apparent. The lack of neuroprotection by AMPT and reserpine, alone and in combination, in studies that control for the effects of these drugs on core temperature, suggests that DA per se is not essential for the expression of MDMA-induced 5-HT neurotoxicity.     

Electrical coupling between the human serotonin transporter and voltage-gated Ca channels

Monoamine transporters have been implicated in dopamine or serotonin release in response to abused drugs such as methamphetamine or ecstasy (MDMA). In addition, monoamine transporters show substrate-induced inward currents that may modulate excitability and Ca²⁺ mobilization, which could also contribute to neurotransmitter release. How monoamine transporters modulate Ca²⁺ permeability is currently unknown. We investigate the functional interaction between the human serotonin transporter (hSERT) and voltage-gated Ca²⁺ channels (Ca_V). We introduce an excitable expression system consisting of cultured muscle cells genetically engineered to express hSERT. Both 5HT and S(+)MDMA depolarize these cells and activate the excitation-contraction (EC)-coupling mechanism. However, hSERT substrates fail to activate EC-coupling in Ca_V1.1-null muscle cells, thus implicating Ca²⁺ channels. Ca_V1.3 and Ca_V2.2 channels are natively expressed in neurons. When these channels are co-expressed with hSERT in HEK293T cells, only cells expressing the lower-threshold L-type Ca_V1.3 channel show Ca²⁺ transients evoked by 5HT or S(+)MDMA. In addition, the electrical coupling between hSERT and Ca_V1.3 takes place at physiological 5HT concentrations. The electrical coupling between monoamine neurotransmitter transporters and Ca²⁺ channels such as Ca_V1.3 is a novel mechanism by which endogenous substrates (neurotransmitters) or exogenous substrates (like ecstasy) could modulate Ca²⁺-driven signals in excitable cells.     

Short- and long-term effects of (+)-methamphetamine and (+/-)-3,4-methylenedioxymethamphetamine on monoamine and corticosterone levels in the neonatal rat following multiple days of treatment

Rats treated with (±)-3,4-methylenedioxymethamphetamine (MDMA) or (+)-methamphetamine (MA) neonatally exhibit long-lasting learning impairments (i.e., after treatment on postnatal days (P)11–15 or P11–20). Although both drugs are substituted amphetamines, they each produce a unique profile of cognitive deficits (i.e., spatial vs. path integration learning and severity of deficits) which may be the result of differential early neurochemical changes. We previously showed that MA and MDMA increase corticosterone (CORT) and MDMA reduces levels of serotonin (5-HT) 24 h after treatment on P11, however, learning deficits are seen after 5 or 10 days of drug treatment, not just 1 day. Accordingly, in the present experiment, rats were treated with MA or MDMA starting on P11 for 5 or 10 days (P11–15 or P11–20) and tissues collected on P16, P21, or P30. Five-day MA administration dramatically increased CORT on P16, whereas MDMA did not. Both drugs decreased hippocampal 5-HT on P16 and P21, although MDMA produced larger reductions. Ten-day treatment with either drug increased dopamine utilization in the neostriatum on P21, whereas 5-day treatment had no effect. No CORT or brain 5-HT or dopamine changes were found with either drug on P30. Although the monoamine changes are transient, they may alter developing neural circuits sufficiently to permanently disrupt later learning and memory abilities.     

Augmentation of serotonin release by sustained exposure to MDMA and methamphetamine in rat organotypic mesencephalic slice cultures containing raphe serotonergic neurons

Several lines of evidence suggest the involvement of the raphe-serotonergic neurons in addiction to psychostimulants and some recreational drugs. In this study, we established rat organotypic mesencephalic slice cultures containing the raphe nuclei and examined the effects of sustained exposure to 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH). Immunostaining for tryptophan hydroxylase (TPH) studies revealed that serotonergic neurons were abundant in the slice cultures. Sustained exposure to MDMA and METH (1-1000 microM) for 4 days had little effect on the serotonin tissue content, [(3)H]citalopram binding, or expression/phosphorylation of TPH. Treatment with MDMA or METH for 30 min increased serotonin release in a concentration-dependent manner. Slice cultures were exposed to MDMA for 4 days following a 1-day withdrawal period and then challenged with MDMA (10 microM). Sustained MDMA exposure augmented MDMA-induced serotonin release in a concentration-dependent manner, indicating serotonergic sensitization. Similar serotonergic sensitization was observed for METH. The development of MDMA-induced serotonergic sensitization was attenuated by the NMDA receptor antagonist, MK-801 (10 microM). These results suggest that in mesencephalic slice cultures sustained MDMA or METH exposure induces serotonergic sensitization through activation of NMDA receptors without serotonergic neurotoxicity. The in vitro model system could help to elucidate the mechanisms underlying drug addiction.     

Enhancement of 3,4-methylenedioxymethamphetamine neurotoxicity by the energy inhibitor malonate

The acute and long-term effects of the local perfusion of 3,4-methylenedioxymethamphetamine (MDMA) and the interaction with the mitochondrial inhibitor malonate (MAL) were examined in the rat striatum. MDMA, MAL or the combination of MAL with MDMA was reverse dialyzed into the striatum for 8 h via a microdialysis probe while extracellular dopamine (DA) and serotonin (5-HT) were measured. One week later, tissue immediately surrounding the probe was assayed for DA and 5-HT tissue content. Local perfusion of MDMA increased DA and 5-HT release but did not produce long-term depletion of DA or 5-HT in tissue. Malonate also increased both DA and 5-HT release but, in contrast to MDMA, produced only long-term depletion of DA. The combined perfusion of MDMA/MAL synergistically increased the release of DA and 5-HT and produced long-term depletion of both DA and 5-HT in tissue. These results support the conclusion that DA, compared with 5-HT, neurons are more susceptible to mitochondrial inhibition. Moreover, MDMA, which does not normally produce DA depletion in the rat, exacerbated MAL-induced DA depletions. The effect of MDMA in combination with MAL to produce 5-HT depletion suggests a role for bio-energetic stress in MDMA-induced toxicity to 5-HT neurons. Overall, these results highlight the importance of energy balance to the function of DA and 5-HT neurons and to the toxic effects of MDMA.     

Methamphetamine and MDMA (ecstasy) neurotoxicity: 'of mice and men'

Methamphetamine (METH) and 3,4-meythylenedioxymethamphetamine (MDMA; 'ecstasy') are currently major drugs of abuse. One of the major concerns of amphetamines abuse is their potential neurotoxic effect on dopaminergic and serotonergic neurons. Although data from human studies are somewhat limited, compelling evidence suggests that these drugs cause neurotoxicity in rodents and primates. Recent studies in transgenic and knockout mice identified the role of dopamine transporters, nitric oxide, apoptotic proteins, and inflammatory cytokines in amphetamines neurotoxicity. Further research into the mechanisms underlying the dopaminergic and serotonergic neurotoxicity and the behavioral corollaries of these neuronal insults could facilitate our understanding of the consequences of human abuse of METH and MDMA on cognition, drug-seeking behavior, extinction and relapse.     

Bath salts and synthetic cathinones: An emerging designer drug phenomenon

Synthetic cathinones are an emerging class of designer drugs abused for psychostimulant and hallucinogenic effects similar to cocaine, methylenedioxymethamphetamine (MDMA), or other amphetamines. Abuse of synthetic cathinones, frequently included in products sold as ‘bath salts’, became prevalent in early 2009, leading to legislative classification throughout Europe in 2010 and schedule I classification within the United States in 2011. Recent pre-clinical and clinical studies indicate that dysregulation of central monoamine systems is a principal mechanism of synthetic cathinone action and presumably underlie the behavioral effects and abuse liability associated with these drugs. This review provides insight into the development of synthetic cathinones as substances of abuse, current patterns of their abuse, known mechanisms of their action and toxicology, and the benefits and drawbacks of their classification.